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Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing

Introduction: Hypospadias [MIM: 300633] is one of the most frequent congenital malformations of male external genitalia. The spectrum of genetic variants causing hypospadias is varied, with studies commonly implicating genes critical in the fetal steroidogenic pathway. This is the first genetic stud...

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Autores principales: Almaramhy, Hamdi Hameed, Abdul Samad, Firoz, Al-Harbi, Ghadeer, Zaytuni, Dimah, Imam, Syed Nazar, Masoodi, Tariq, Shamsi, Monis Bilal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10297146/
https://www.ncbi.nlm.nih.gov/pubmed/37384334
http://dx.doi.org/10.3389/fgene.2023.1106933
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author Almaramhy, Hamdi Hameed
Abdul Samad, Firoz
Al-Harbi, Ghadeer
Zaytuni, Dimah
Imam, Syed Nazar
Masoodi, Tariq
Shamsi, Monis Bilal
author_facet Almaramhy, Hamdi Hameed
Abdul Samad, Firoz
Al-Harbi, Ghadeer
Zaytuni, Dimah
Imam, Syed Nazar
Masoodi, Tariq
Shamsi, Monis Bilal
author_sort Almaramhy, Hamdi Hameed
collection PubMed
description Introduction: Hypospadias [MIM: 300633] is one of the most frequent congenital malformations of male external genitalia. The spectrum of genetic variants causing hypospadias is varied, with studies commonly implicating genes critical in the fetal steroidogenic pathway. This is the first genetic study on hypospadias from the Yemen ethnicity and the second to report HSD3B2 mutations in more than one affected individual from the same family. Material and methods: Surgical hypospadias repair was performed on two hypospadias-affected siblings from a consanguineous family. Whole-exome sequencing (WES) was performed to identify the potential pathogenic variant for hypospadias, which was later confirmed by Sanger sequencing. The identified variant was further analyzed for its pathogenicity by using in silico tools such as SIFT, PolyPhen-2, MutationAssessor, MutationTaster, FATHMM, and ConSurf. Results: We identified a novel missense mutation (Chr1:119964631T>A, c.507T>A, p. N169K) in 3β-hydroxysteroid 2-dehydrogenase (HSD3B2) gene by WES. Sanger sequencing confirmed that the variant segregated the disease in the family between the affected and non-affected individuals. Both patients are homozygous, while parents and two unaffected siblings are heterozygous carriers, indicating an autosomal recessive pattern of inheritance. The in silico analysis by all six in silico tools (SIFT, PolyPhen-2, MutationAssessor, MutationTaster, FATHMM, and ConSurf) predicted the variant to be pathogenic/deleterious. Discussion: An abnormal fetal steroidogenic pathway due to genetic influences may affect the development of the male genital tract, including the urethral tract closure and morphogenesis of male genitalia. Furthermore, the pathogenicity of the observed variant in this study, confirmed by multiple in silico tools, characterizes the influence HSD3B2 gene variants may have in the etiology of hypospadias. Conclusion: Understanding of pathogenic manifestation and inheritance of confounding genetic variants in hypospadias is a matter of great concern, especially in familial cases.
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spelling pubmed-102971462023-06-28 Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing Almaramhy, Hamdi Hameed Abdul Samad, Firoz Al-Harbi, Ghadeer Zaytuni, Dimah Imam, Syed Nazar Masoodi, Tariq Shamsi, Monis Bilal Front Genet Genetics Introduction: Hypospadias [MIM: 300633] is one of the most frequent congenital malformations of male external genitalia. The spectrum of genetic variants causing hypospadias is varied, with studies commonly implicating genes critical in the fetal steroidogenic pathway. This is the first genetic study on hypospadias from the Yemen ethnicity and the second to report HSD3B2 mutations in more than one affected individual from the same family. Material and methods: Surgical hypospadias repair was performed on two hypospadias-affected siblings from a consanguineous family. Whole-exome sequencing (WES) was performed to identify the potential pathogenic variant for hypospadias, which was later confirmed by Sanger sequencing. The identified variant was further analyzed for its pathogenicity by using in silico tools such as SIFT, PolyPhen-2, MutationAssessor, MutationTaster, FATHMM, and ConSurf. Results: We identified a novel missense mutation (Chr1:119964631T>A, c.507T>A, p. N169K) in 3β-hydroxysteroid 2-dehydrogenase (HSD3B2) gene by WES. Sanger sequencing confirmed that the variant segregated the disease in the family between the affected and non-affected individuals. Both patients are homozygous, while parents and two unaffected siblings are heterozygous carriers, indicating an autosomal recessive pattern of inheritance. The in silico analysis by all six in silico tools (SIFT, PolyPhen-2, MutationAssessor, MutationTaster, FATHMM, and ConSurf) predicted the variant to be pathogenic/deleterious. Discussion: An abnormal fetal steroidogenic pathway due to genetic influences may affect the development of the male genital tract, including the urethral tract closure and morphogenesis of male genitalia. Furthermore, the pathogenicity of the observed variant in this study, confirmed by multiple in silico tools, characterizes the influence HSD3B2 gene variants may have in the etiology of hypospadias. Conclusion: Understanding of pathogenic manifestation and inheritance of confounding genetic variants in hypospadias is a matter of great concern, especially in familial cases. Frontiers Media S.A. 2023-06-13 /pmc/articles/PMC10297146/ /pubmed/37384334 http://dx.doi.org/10.3389/fgene.2023.1106933 Text en Copyright © 2023 Almaramhy, Abdul Samad, Al-Harbi, Zaytuni, Imam, Masoodi and Shamsi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Almaramhy, Hamdi Hameed
Abdul Samad, Firoz
Al-Harbi, Ghadeer
Zaytuni, Dimah
Imam, Syed Nazar
Masoodi, Tariq
Shamsi, Monis Bilal
Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing
title Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing
title_full Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing
title_fullStr Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing
title_full_unstemmed Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing
title_short Identification of a novel candidate HSD3B2 gene variant for familial hypospadias by whole-exome sequencing
title_sort identification of a novel candidate hsd3b2 gene variant for familial hypospadias by whole-exome sequencing
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10297146/
https://www.ncbi.nlm.nih.gov/pubmed/37384334
http://dx.doi.org/10.3389/fgene.2023.1106933
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